A study in The American Journal of Pathology has found that promoting autophagy, the process by which cells break down and destroy damaged or abnormal proteins, with rapamycin, an immunosuppressant, reduces intestinal epithelial cell death and restores intestinal barrier function during sepsis. It also suggests that the interaction of the mammalian target of rapamycin (mTOR), a negative regulator of autophagy, and pole-like kinase 1 (PLK1) is crucial in sepsis-induced barrier dysfunction and may provide new insights for the treatment of sepsis.
In the study, mice underwent cecal ligation and puncture (CLP), a perforation of the cecum that allows the release of fecal material into the peritoneal cavity, establishing an in vivo model of sepsis. Compared with mice in the sham group, CLP mice suffered from severe intestinal mucosal injury and increased intestinal mucosal permeability. Under rapamycin treatment, autophagy activation inhibited enterocyte apoptosis and restored the disrupted intestinal barrier, suggesting that autophagy plays a protective role in sepsis-induced intestinal barrier dysfunction.
To determine whether the protective role of PLK is based on autophagy, PLK1 gene-modified mice (CAG-PLK1 mice) were subjected to CLP. Activation of autophagy was observed and apoptosis was alleviated. However, these amelioration phenomena were worsened in mice treated with chloroquine, an autophagy inhibitor, compared to mice treated with rapamycin. These results indicate that PLK1 protects against sepsis-induced barrier dysfunction by promoting intestinal autophagy.
To further explore whether PLK1 promotes autophagy via the mTOR pathway in intestinal epithelial cells, the researchers looked at the physical interaction between PLK1 and mTOR in an in vitro model of human colonic epithelial cells. They found that PLK1 also promotes cellular autophagy and enhances autophagy and high permeability. Furthermore, PLK1 physically interacted with mTOR and participated in cross-regulatory crosstalk in intestinal cells during sepsis.
These findings indicate that the PLK1-mTOR axis may be a promising therapeutic target for the treatment of sepsis.